The role of the adventitia in vascular inflammation

Abstract

Traditional concepts of vascular inflammation are considered "inside-out" responses centered on the monocyte adhesion and lipid oxidation hypotheses. These mechanisms likely operate in concert, holding the central tenet that the inflammatory response is initiated at the luminal surface. However, growing evidence supports a new paradigm of an "outside-in" hypothesis, in which vascular inflammation is initiated in the adventitia and progresses inward toward the intima. Hallmarks of the outside-in hypothesis include population of the adventitia with exogenous cell types, including monocytes, macrophages, and lymphocytes, the phenotypic switch of adventitial fibroblasts into migratory myofibroblasts, and increased vasa vasorum neovascularization. The resident and migrating cells deposit collagen and matrix components, respond to and upregulate inflammatory chemokines and/or antigens, and regulate the local redox state of the adventitia. B cells and T cells generate local humoral immune responses against local antigen presentation by foam cells and antigen presenting cells. These events result in increased local expression of cytokines and growth factors, evoking an inflammatory response that propagates inward toward the intima. Ultimately, it appears that the basic mechanisms of cellular activation and migration in vascular inflammation are highly conserved across a variety of cardiovascular disease states and that major inflammatory events begin in the adventitia.

Figure 1

The role of the adventitia in vascular inflammation in an arterial cross section. Moving from left to right, depicting the healthy adventitia, the phenotypic switch from fibroblast to myofibroblast, adhesion molecular, lipid oxidation, generation of foam cells, B cell maturation and contribution to the local humoral immune response, and transmigration of monocytes into the arterial media. According to the outside-in hypothesis, inflammatory cues, perhaps in the form of a focal elastic laminae tear or chronic inflammation products, such as leukotrienes and chemokines, signal the adventitial fibroblast (FB) to undergo a phenotypic switch into a migratory myofibroblast (myoFB) in a transforming growth factor-β (TGF-β), dependent manner. The myoFB transforms into a contractile myoFB (cmFB). The cmFB generates additional cytokines, such as CCL2, eventually undergoing apoptosis by a redox mechanism. The remaining adventitial FB cells also secrete cytokines to recruit a massive influx of exongenous leukocytes. FBs also secrete excess collagen (Col) and extracellular matrix (ECM) to stabilize the artery and perhaps provide additional matrix on which to seed to newly recruited cells. For increased cellular trafficking, the endothelium of the vasa vasorum demonstrates upregulated P-selectin and vascular cell adhesion molecule-1 (VCAM-1). Lymphoid organ-like clusters of lymphoctyes, called B cell maturation centers, are where local humoral immune responses are generated. Antibodies against inflammatory antigens, presented by antigen presenting cells (APCs) are produced in these lymphoid clusters. APCs also interact with and activate T cells, which then transform into proinflammatory Th1 cells. The cytokines and antigens produced by activated lymphocytes serve as chemoattractants to promote the monocyte transmigration through the endothelium and subsequent transformation into macrophages. Macrophages uptake oxidized LDL (oxLDL) and transform into foam cells and the apoptotic bodies resulting from foam cell death produce additional inflammatory antigens, release oxLDL, and modify the redox state of the local environment. At this point, outside-in and inside-out mechanisms collide in the vascular inflammatory cascade.